Many studies demonstrate that environmental chemicals impair the mammalian immune system. Mechanisms responsible for this immunotoxicity are poorly understood. Furthermore, little is known about the effects of environmental chemicals on lymphopoiesis, the process of lymphocyte development. To model the effects of ubiquitous environmental chemicals on blood cell development, modulation of B lymphocyte development by polycyclic aromatic hydrocarbons (PAH) in long term murine bone marrow cultures has been studied. This simulation of B lymphopoiesis is invaluable since it closely mimics conditions required in vivo for B cell development. Previous studies demonstrated that PAH immunotoxicity can be attributed to induction of apoptosis in bone marrow-derived preB cells. PreB cell death is induced at low pH doses, is controlled by the aryl hydrocarbon receptor/transcription factor (AhR) and/or genes regulated by the AhR, and is mediated indirectly through AhR+ stromal cells constituting the hematopoietic microenvironment. Interestingly, PAH-induced apoptosis closely resembles the process by which developing immune systems are purged of pathologic autoimmune lymphocytes. Since the immune system begins to program responsiveness to a constellation of antigenic insults at this developmental state, these results suggest that PAH exposure could compromise human immune defenses against microbes and tumors, the latter induced in part as a result of environmental chemical exposure. Given the importance of these findings to environmental health, three specific goals are proposed: 1) to investigate mechanism of PAH-induced, AhR-mediated stromal cell dysfunction, 2) to define intracellular preB cell signals resulting in apoptosis, and 3) to confirm and extend model systems by establishing in vivo correlates using AhR wild-type and mutant mouse strains. Proposed studies will emphasize the role of transcription factors in generating a death signal within lymphopoetic stromal cells and in the activation of the preB cell death program. Results will not only allow a direct comparison between autoantigen-and PAH-induced intracellular apoptotic signals, but will provide a solid foundation on which to base future studies on molecular mechanism of PAH dysregulated cytokine production, lymphocyte adhesion and cellular proliferation.